2. Academic Validation
  3. Macrophage TRIM21 lactylation exacerbates infection-induced orchitis through enhancing STAT1-mediated CXCL9 and CXCL10 production

Macrophage TRIM21 lactylation exacerbates infection-induced orchitis through enhancing STAT1-mediated CXCL9 and CXCL10 production

  • Front Immunol. 2026 Jan 14:16:1684836. doi: 10.3389/fimmu.2025.1684836.
Wenjing Tang # 1 2,  Wenjie Chen # 1,  Na Li # 1,  Wei Li # 3,  Zhigang Lei # 1,  Wenhui Sun 1,  Xuan Xie 1,  Yihong Jiang 1,  Ying Chen 1,  Lei Xu 1,  Jifeng Zhu 1,  Yalin Li 1,  Jiahao Sha 4,  Yang Dai 5,  Sha Zhou 1,  Xiaojun Chen 6,  Chuan Su 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Reproductive Medicine and Offspring Health, National Vaccine Innovation Platform of Nanjing Medical University, Key Laboratory for Pathogen Infection and Control of Jiangsu Province, Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 2 Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 4 State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 5 National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Provincial Medical Key Laboratory, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, China.
  • 6 Key Laboratory for Pathogen Infection and Control of Jiangsu Province, Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Nanjing, Jiangsu, China.
  • # Contributed equally.
PMID: 41613144 DOI: 10.3389/fimmu.2025.1684836
Abstract

Introduction: Infection-induced orchitis, a leading cause of acquired male infertility affecting 8%-12% of couples globally, is driven by unresolved inflammatory responses following Bacterial infection.

Methods: We employed uropathogenic Escherichia coli (UPEC)- and lipopolysaccharide (LPS)-induced orchitis models to define the mechanisms underlying testicular inflammation. We interrogated the cellular sources of CXCL9/CXCL10 and assessed macrophage-driven inflammatory cell recruitment and spermatogenic disruption. Mechanistic studies were focused on lysine lactylation, STAT1 protein stability, ubiquitin-proteasome-mediated degradation, and the role of the E3 ubiquitin Ligase TRIM21.

Results: We demonstrate that macrophages are the predominant source of CXCL9 and CXCL10 responsible for recruiting inflammatory cells into the testis, thereby disrupting spermatogenesis. Mechanistically, the lysine lactylation in macrophages promotes STAT1-mediated CXCL9 and CXCL10 expression by inhibiting ubiquitin-proteasome pathway-mediated STAT1 degradation. Specifically, K345 lactylation of the E3 ubiquitin Ligase TRIM21 attenuates ubiquitin-proteasome pathway-mediated STAT1 degradation in macrophages by preventing its interaction with STAT1.

Discussion: This study provides the first evidence that non-histone lactylation (TRIM21 K345) exacerbates inflammatory orchitis and highlights TRIM21 lactylation or CXCL9/10 as promising therapeutic targets for infection-associated male infertility.

Keywords

CXCL9 and CXCL10; TRIM21; infection-induced orchitis; lactylation; macrophage.

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